Cilostazol increases 3T3-L1 preadipocyte differentiation with improved glucose uptake associated with activation of peroxisome proliferator-activated receptor-gamma transcription

Atherosclerosis. 2008 Dec;201(2):258-65. doi: 10.1016/j.atherosclerosis.2008.02.006. Epub 2008 Feb 15.

Abstract

In the present study, we assessed that cilostazol stimulates differentiation of 3T3-L1 fibroblasts into adipocytes, and to improve insulin sensitivity in conjunction with PPARgamma transcriptional activity. Upon treatment of COS-7 cells and human umbilical vein endothelial cells (HUVECs) with cilostazol (10 and 30 microM), endogenous PPARgamma transcriptional activity was significantly elevated in both cells as did rosiglitazone (10 microM), and these effects were suppressed by 5 microM GW9662, an antagonist of PPARgamma activity. Cilostazol-induced 3T3-L1 fibroblast differentiation into adipocytes in concert with increases in expression of PPARgamma responsive genes such as CCAAT enhancer binding protein alpha (C-EBPalpha), aP2, which were accompanied by increased adiponectin and decreased resistin expressions as did rosiglitazone. These variables were strongly suppressed by GW9662, indicative of a PPARgamma-mediated signaling. GLUT4 protein expression and glucose uptake were significantly elevated by cilostazol as was by rosiglitazone, which were also attenuated by GW9662, indicative of improvement of insulin sensitivity. Signaling pathways involved in the cilostazol-stimulated PPARgamma transcription activity in HUVECs included phosphatidylinositol 3-kinase (PI3-kinase)/AKT. Taken together, it is suggested that cilostazol increases differentiation of 3T3-L1 fibroblasts into adipocytes, and improves insulin sensitivity by stimulating PPARgamma transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Anilides / pharmacology
  • Animals
  • COS Cells
  • Cell Differentiation
  • Chlorocebus aethiops
  • Cilostazol
  • Fibroblasts / metabolism
  • Glucose / metabolism*
  • Glucose Transporter Type 4 / metabolism
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Mice
  • PPAR gamma / metabolism*
  • Phosphodiesterase Inhibitors / pharmacology
  • Rosiglitazone
  • Tetrazoles / pharmacology*
  • Thiazolidinediones / pharmacology

Substances

  • 2-chloro-5-nitrobenzanilide
  • Anilides
  • Glucose Transporter Type 4
  • Hypoglycemic Agents
  • PPAR gamma
  • Phosphodiesterase Inhibitors
  • Slc2a4 protein, mouse
  • Tetrazoles
  • Thiazolidinediones
  • Rosiglitazone
  • Glucose
  • Cilostazol